What is MODY? (Maturity-Onset Diabetes of the Young)

• Monogenic diabetes caused by a single-gene mutation; inheritance is autosomal-dominant (each child of an affected parent has a 50 % risk).

• Typically presents before age 25–30 but can appear later.

• Accounts for ≈ 1–2 % of all diabetes cases—even a small practice is likely to have at least one patient.

Key issue	Why it’s important to you & your patients
🚩 Misclassification	Up to 90 % of people with MODY are initially coded as type 1 or type 2 diabetes—so opportunities for tailored care are missed. diabetes.org.uk
💊 Precision treatment	Common sub-types (HNF1A/4A) respond to tiny doses of sulfonylurea, while GCK-MODY often needs no drug therapy—accurate diagnosis can stop unnecessary lifelong insulin and daily finger-pricks. diabetesgenes.org
👪 Cascade testing	Because MODY is autosomal-dominant, one correct diagnosis prompts targeted genetic testing for relatives and early intervention. diabetesgenes.orgdiabetes.org.uk
📚 Curriculum relevance	The RCGP Metabolic Problems & Endocrinology guide lists “rarer types such as MODY” as core knowledge for AKT, CSA & WPBA—so examiners expect you to spot it. rcgp.org.uk

When should you suspect MODY in primary care?

Think Maturity-Onset Diabetes of the Young when a lean young adult (often < 25 y) develops non-ketotic hyper-glycaemia, has a striking vertical family history of diabetes, and retains measurable C-peptide with absent auto-antibodies several years after diagnosis. Identifying these clues early enables precision therapy (e.g. low-dose sulfonylurea or no medication at all) and cascade testing for relatives.

Clinical clue	Why it points to MODY
Diagnosis ≤ 25 y	Early-onset, non-ketotic diabetes typical of monogenic β-cell defects.
Vertical family history (≥ 2 generations)	Autosomal-dominant inheritance → 50 % risk to each child.
Non-obese / minimal metabolic features	Lack of insulin resistance helps distinguish from classic type 2 diabetes.
Non-insulin dependent at diagnosis	Endogenous insulin still present; some subtypes respond to low-dose sulfonylureas.
Islet auto-antibodies ↓ / C-peptide ↑ ≥ 3 y post-dx	Negative antibodies and preserved C-peptide help exclude autoimmune type 1 diabetes.
Stable mild fasting glucose ↑ (5.5–8 mmol/L)	Typical of GCK-MODY, which rarely needs pharmacological treatment.

Autosomal-dominant inheritance—why it matters in MODY

• One faulty copy is enough – MODY genes sit on the autosomes (non-sex chromosomes). If just one parent carries the variant, only a single copy is needed for the child to develop the condition. diabetesgenes.org

• 50 % risk for every pregnancy – Each son or daughter has a 1-in-2 chance of inheriting the same variant, regardless of sex. genomicseducation.hee.nhs.uk

• “Vertical” family pattern – Diabetes typically appears in consecutive generations (grandparent → parent → child), a hallmark clinical clue for MODY. genomicseducation.hee.nhs.uk

• Cascade testing opens doors – Spotting one case triggers targeted genetic testing for first-degree relatives, allowing early diagnosis, tailored treatment or reassurance if negative. nw-gmsa.nhs.uk

Genetic subtypes every GP should recognise

Subtype (gene)	Key clinical notes
HNF1A-MODY (MODY 3)	Commonest form (≈ 50–70 %). Progressive ↑ glycaemia from teens/20s, ↓ renal glucose threshold → early glycosuria. Marked sulfonylurea sensitivity (e.g. gliclazide 20–40 mg); many discontinue insulin.
GCK-MODY (MODY 2)	Lifelong, stable mild fasting glucose ↑ (5.5–8 mmol/L); usually asymptomatic. No drug therapy needed outside pregnancy.
HNF4A-MODY (MODY 1)	Phenotype similar to HNF1A but rarer. Responds to low-dose sulfonylurea; watch for ↑ birth-weight & neonatal hypoglycaemia. Some progress to insulin later.
HNF1B-MODY (MODY 5 / RCAD)	Diabetes plus renal cysts, genital tract malformations, gout. Often requires early insulin. Always screen renal function & involve nephrology.
Rarer genes (e.g. KCNJ11, ABCC8, INS, PDX1)	Together < 5 % of MODY. Some (KCNJ11/ABCC8) respond well to sulfonylureas—consider in neonatal or atypical cases.

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  Primary-care investigation pathway for suspected MODY 

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  • Confirm diabetes

    • WHO diagnostic thresholds:

      • Fasting plasma glucose ≥ 7 mmol/L (≥ 126 mg/dL)

      • 2-h OGTT glucose ≥ 11.1 mmol/L (≥ 200 mg/dL)

      • HbA1c ≥ 48 mmol/mol (≥ 6.5 %)

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  • Run the “triage pair” in surgery

    1. Islet auto-antibodies ↓ – request GAD & IA-2; absence argues against type 1 diabetes.

    2. Random C-peptide ≥ 200 pmol/L (check ≥ 3 years after diagnosis) – indicates preserved endogenous insulin.

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  • Apply MODY suspicion criteria – onset < 35 y, strong vertical family history, non-obese, insulin-independent, antibody-negative, C-peptide preserved.

  • Quantify the odds – use the free Exeter MODY probability calculator to support referral/testing decisions.

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  • Order genomic testing when criteria met

    • R141 – MODY / monogenic diabetes (post-neonatal)

    • R143 – Neonatal diabetes or suspicion arising in pregnancy
      (Both tests are listed in the NHS National Genomic Test Directory.)

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  • Refer or discuss with your regional monogenic diabetes clinic / genomic laboratory hub if uncertain.

  • Think family – explain the 50 % autosomal-dominant risk and arrange cascade testing for first-degree relatives after a pathogenic variant is confirmed.

  • Tip for GCK-MODY – a fasting glucose 5.5–8 mmol/L (99–144 mg/dL) in a lean patient (< 30 kg/m²) is now an explicit NHS trigger for genomic testing.

  
  

• Core management headlines for MODY in UK general practice

  • Start with the basics – Offer the same lifestyle package (healthy diet, regular activity, smoking cessation) you give every person with diabetes, alongside cardiovascular-risk management. NICE

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  • Let the gene dictate the drug

    • GCK-MODY (MODY 2) – Usually needs no glucose-lowering therapy; treat only in pregnancy if the fetus is unaffected. PMCFrontiers

    • HNF1A- & HNF4A-MODY (MODY 3 & 1) – First-line low-dose sulfonylurea (e.g. gliclazide 20–40 mg); many patients can stop insulin altogether. PMCDiabetes JournalsFrontiers

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    • HNF1B-MODY (MODY 5/RCAD) – Often needs early insulin plus renal surveillance (U&Es and periodic renal ultrasound). genomicseducation.hee.nhs.ukactionability.clinicalgenome.org

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  • Pregnancy is a special case – Urgently involve a maternity diabetes/genetics team if GCK-MODY is suspected; fetal genotype drives treatment and glibenclamide is usually ineffective. FrontiersFrontiers

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  • Annual review still matters – Complete the standard 9 NICE care processes and add subtype-specific checks (e.g. renal US every 3–5 y in HNF1B). NICEgenomicseducation.hee.nhs.uk

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  • Work as an MDT – Coordinate with genetic diabetes nurses, maternity services, renal or paediatric colleagues, and the regional genomic laboratory hub for testing (R141/R143 panels). england.nhs.uk

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  • Think family – Explain 50 % autosomal-dominant risk and arrange cascade testing for first-degree relatives once a pathogenic variant is confirmed. diabetesgenes.org

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  Bottom line: Accurate genetic diagnosis drives precision therapy, avoids unnecessary insulin, guides pregnancy care and protects the wider family—so suspect MODY early and manage by the gene, not the glucose number.

Take-home summary

• Don’t manage in isolation: Definitive MODY diagnosis rests on gene testing that most GP surgeries can’t order directly—link up early with your regional monogenic diabetes / endocrine genetics team.

• Refer when suspicion is high: A lean young adult with preserved C-peptide, negative antibodies and a multigenerational history should trigger urgent secondary-care referral for targeted genomic testing (R141/R143 panels).

• Share care, not responsibility: Once the subtype is confirmed, specialists can advise on drug choice, pregnancy planning and cascade testing, while primary care maintains routine reviews and long-term cardiovascular risk management.

• Think family: Every confirmed case unlocks preventive care for relatives—early specialist involvement ensures the right people are tested and counselled.

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